Virginiamycin mixture

ABSTRACT

A mixture comprising:  
     a) virginiamycin:  
     b) a pharmaceutically acceptable and substantially anhydrous wetting agent including sodium lauryl sulfate;  
     c) a sufficient amount of pharmaceutically acceptable buffering agent to provide a pH of from about 3 0 to about 7 0 when said mixture IS added to water; and  
     d) from about 0.5 weight percent to about 10 0 weight percent colloidal silicon dioxide.  
     wherein the ratio of the weight percent of (b) to the weight percent of (a) percent by weight is at least about 1.5:1.  
     The mixture is designed to be added to water to produce a stable suspension of the virginiamycin, which can then be applied to, for example, feed grain.

[0001] This non-provisional application is based upon and claimspriority from Provisional Application No 60/020,512 filed Jul. 1 1996.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a mixture comprisingvirginiamycin

[0003] Virginiamycin antibiotics, in their most effective form, includeboth M and S components. Coccito, Micro Rev., 43, 145 (1979).Virginiamycin has been used as an antibacterial and in the prevention oflactic acidosis (e.g. U.S. Pat. Nos. 5,137,900 and 5,242,938 and TheMerck Index, 12th Edition, pages 1707-1708). It has also been used inthe form of a feed additive to improve growth in poultry, swine, andcattle. A possible mechanism for its use as a growth promotant couldrelate to an inhibition of intestinal flora. Coccito, supra.Virginiamycin's widely accepted use stems from having low toxicity,minimal production of resistant mutant strains, quick degradation infeces, and minimal tissue retention.

[0004] Wettable powders have been used for the administration of variousinsecticides and herbicides.

SUMMARY OF THE INVENTION

[0005] The present invention relates to a mixture comprising:

[0006] a) virginiamycin;

[0007] b) a pharmaceutically acceptable surfactant including sodiumlauryl sulfate; p1 c) a sufficient amount of pharmaceutically acceptablebuffering agent to provide a pH of from about 3.0 to about 7.0 when saidmixture is added to water, and

[0008] d) from about 0.5 weight percent to about 10.0 weight percentcolloidal silicon dioxide,

[0009] wherein the ratio of the weight percent of (b) to the weightpercent of (a) is at least about 1.5:1.

DETAILED DESCRIPTION

[0010] The mixture comprising virginiamycin is in the form of awettable-type powder. The powder mixture can be added to water,including some forms of hard water, to produce a stable suspension ofthe virginiamycin, which can then be, for example. dilivered directly toa patient (e.g orally) or applied to, for example, food stuffs such asfeed grain. The feed grain is then fed to animals. for example livestockand poultry thereby administering the virginiamycin The mixture shouldpreferably be substantially anhydrous so as to maximize the shelf lifeof the mixture prior to forming the water suspension.

[0011] Virginiamycin can be produced using known methods, for examplefermentation. For example. virginiamycin M can be produced byfermentation of a streptomyces species originally isolated from Indiansoil samples and deposited with the American Type Culture Collection,12301 Parklawn Drive, Rockville, Md. 20852, U.S.A. on Jul. 29, 1986 andassigned ATCC number 53527 U.S. Pat. No. 5.242,938.

[0012] Dose levels of virginiamycin are known in the art and can varydue to a number of factors, including, for example, compound activity,the route of administration, the time of administration, diseaseseverity, excretion rate, combination of other drugs, as well as theage, body weight, sex, diet, and general health of the patient beingtreated Generally, for example, with a human subject, the dailyeffective dose can range from about 1.0 mg to about 1500 mg, preferablyabout 10 mg to about 500 mg, in single or divided doses. For a domesticanimal, the effective dose can range from about 5 to about 200 parts permillion per volume of food. U.S. Pat. No. 5,242,938.

[0013] For veterinary purposes, dosage levels known in the art can alsobe found, for example, in the 1996 Feed Additive Compendium, MillerPublishing Co. (1996), pp 324-328.

[0014] The claimed mixture comprises virginiamycin, preferablysubstantially pure, and a pharmaceutically acceptable surfactant, sodiumlauryl sulfate (SLS), preferably substantially anhydrous and granulated.The ratio of the weight percent of SLS to the weight percent ofvirginiamycin should be at least about 1.5 to 1, preferably about 1.54to 1. Substantially pure virginiamycin has an activity of about 200%(plus or minus 20%) as measured by methods known in the art (Gossele, etal., Analyst, 116, 1373 (1991) and Blain, et al., Analyst, 119, 361(1994).

[0015] The powder mixture also includes a pharmaceutically acceptableanti-caking agent, colloidal silicon dioxide, which can act as scavengerfor water as well as a wetting and suspending agent for thevirginiamycin. The amount of colloidal silicon dioxide can range from0.5 weight percent of the mixture to about 10.0 weight percent of themixture, preferably about 2.0 weight percent.

[0016] A pharmaceutically acceptable buffer is also included, forexample phosphate or citrate buffers, preferably citric acid/sodiumcitrate. The amount of buffer should be sufficient to provide a pH offrom about 3.0 to about 7 0, preferably from about 4 0 to about 5.5 whenthe mixture is added to water. Maintenance of pH permits thevirginiamycin to be suspended in a water environment with minimal effecton its activity

[0017] The powder mixture is added to water to form a stable suspensionof the virginiamycin, which is then applied to, for example, feed grain.The amount of mixture dispensed in the water is approximately 4 5% byweight of the suspension.

[0018] A pharmaceutically acceptable water soluble filler material canalso be included Examples include sugars, such as lactose and dextrose,preferably lactose. Such fillers may also effect the flowability of themixture.

[0019] A pharmaceutically acceptable anti-foaming agent, which is, forexample, an emulsion and will not substantially effect the pH of theresulting suspension, can also be included in the anhydrous mixture, forexample, polydimethylsiloxane. Once the suspension is made, theanti-foaming agent minimizes the amount of foam caused by the SLS uponagitation of the suspension. This can be important if, for example, thesuspension is being sprayed and a pump is needed to drive the suspensionthrough the spraying apparatus. The amount of anti-foaming agent in themixture can range from about 0.5 weight percent to about 10.0 weightpercent, preferably about 2.8 weight percent.

[0020] The mixture should preferably be maintained as substantiallyanhydrous prior to forming the suspension in order to minimize thebreakdown of the components of the mixture. As a result of minimizingbreakdown, the shelf life of the mixture can be maximized.

[0021] The mixture is formed by adding its ingredients together andthoroughly blending them together. Once the mixture is formed, asuspension can be made by adding the mixture to water. The resultingsuspension is substantially stable with minimal sedimentation ofvirginiamycin falling out of the suspension for about a day withperiodic stirring or with little or no stirring of the suspension forabout a couple hours, preferably about six hours once the suspension hasbeen properly formed.

[0022] A pharmaceutically acceptable indicator dye can also be included,depending upon acceptable food and drug regulations. The dye, forexample, FD&C blue No. 1 powder, would give a blue color to thesuspension and, in turn, to feed grain sprayed herewith Thus, thetreated grain can be readily identified.

[0023] A preferred formulation of the claimed invention is thefollowing. INGREDIENT FORMULA % W/W Virginiamycin Feed Grade* notavailable 18.8 (activity = about 200%) Sodium Lauryl Sulfate C₁₂H₂₅NaO₄S30.0 Colloidal Silicon Dioxide SiO₂ 2.0 Citric Acid, anhydrous, finegranular C₆H₈O₇ 20.0 Sodium Citrate anhydrous powder C₆H₅N₂₃O₇ 20.0Antifoam AF emulsion [-(CH₃)₂SiO₂]_(n) 2.8 FD&C Blue No. 1 powder FDALot #AG4275 0.4 Warner-Jenkinson Co. Code #05601 Lactose* anhydrous, 80mesh C₁₂H₂₂O₁₁ 6.0

[0024] The following are intended as non-limiting examples of thepresent invention.

EXAMPLE 1

[0025] The below listed ingredients were combined and mixed togetheruntil a uniform mixture was formed. INGREDIENT % w/v AMOUNTVirginiamycin Feed Grade 213% 0.94  9.40 g Sodium Lauryl Sulfate 1.5015.00 g Colloidal Silicon Dioxide 0.10  1.00 g Citric Acid U.S.P. 1.0010.00 g Sodium Citrate U.S.P. 1.00 10.00 g Antifoam A.F. 0.10  1.00 g

[0026] A suspension was formed by adding the above mixture to 900 ml ofdistilled water in a 1 liter graduated cylinder until dispersion wascomplete. Then additional water was added to bring the total volume to 1liter. pH 4 24

EXAMPLE 2

[0027] The below listed ingredients were combined and mixed togetheruntil a uniform mixture was formed. INGREDIENT % w/v AMOUNTVirginiamycin Feed Grade 213% 0.94  9.40 g Sodium Lauryl Sulfate 1.5015.00 g Colloidal Silicon Dioxide 0.10  1.00 g Citric Acid U.S.P. 1.0010.00 g Sodium Citrate U.S.P. 1.00 10.00 g Antifoam A.F. 0.10  1.00 g

[0028] A suspension was formed by adding the above mixture to 900 ml ofdistilled water in a 1 liter graduate until dispersion was complete.Then additional water was added to bring the total volume to 1 liter. pH4.30.

EXAMPLE 3

[0029] The below listed ingredients were placed in a mixer and mixed for15 minutes to form a base mixture. INGREDIENT % w/v AMOUNT Sodium LaurylSulfate 36.9 4500.0 g Citric Acid 24.6 3000.0 g Sodium Citrate 24.63000.0 g Anhydrous Lactose, 80 Mesh (Sheffield) 7.4  900.0 g Antifoam A.F. Emulsion 3.4  420.0 g Colloidal Silicon Dioxide 2.6  300.0 g FD&CBlue No. 1 Powder 0.5  60.0 g

[0030] A. 1126.8 g of virginiamycin animal feed grade (213% activity)(18.8%) was added to 4873.2 g of base mixture (81.2%) in a mixer andmixed for 15 minutes.

[0031] B. 956.1 g of virginiamycin animal feed grade (205% activity)(19.5%) was added to 3943.2 g of base mixture (80.5%) in a mixer andmixed for 15 minutes.

1. A mixture comprising: a) virginiamycin; b) a pharmaceuticallyacceptable surfactant including sodium lauryl sulfate; c) a sufficientamount of pharmaceutically acceptable buffering agent to provide a pH offrom about 3.0 to about 7.0 when said mixture is added to water; and d)from about 0.5 weight percent to about 10 0 weight percent colloidalsilicon dioxide, wherein the ratio of the weight percent of (b) to theweight percent of (a) percent by weight is at least about 1.5:1.
 2. Themixture of claim 1, wherein the ratio of (b) to (a) is about 1.54:1. 3.The mixture of claim 1, wherein the amount of buffer is sufficient toprovide a pH of from about 4.0 to about 5.5 when said mixture is addedto water.
 4. The mixture of claim 1, wherein said buffer includes citricacid and sodium citrate.
 5. The mixture of claim 4, wherein said citricacid and sodium citrate are substantially anhydrous.
 6. The mixture ofclaim 1, further including a pharmaceutically acceptable anti-foamingagent.
 7. The mixture of claim 6, wherein said anti-foaming agent ispolydimethylsiloxane.
 8. The mixture of claim 1, further including apharmaceutically acceptable dye.
 9. The mixture of claim 1, wherein saidvirginiamycin is substantially pure
 10. The mixture of claim 1 whereinsaid mixture is substantially anhydrous.
 11. A substantially anhydrousmixture comprising: a) virginiamycin; b) a pharmaceutically acceptableand substantially anhydrous surfactant including sodium lauryl sulfate;c) a sufficient amount of pharmaceutically acceptable buffering agent toprovide a pH of from about 3.0 to about 7 0 when said mixture is addedto water; and d) from about 0.5 weight percent to about 10.0 weightpercent colloidal silicon dioxide, wherein the ratio of the weightpercent of (b) to the weight percent of (a) percent by weight is atleast about 1.5:1.
 12. The anhydrous mixture of claim 11, wherein theratio of (b) to (a) is about 1.54:1.
 13. The anhydrous mixture of claim11, where the amount of buffer is sufficient to provide a pH of fromabout 4.0 to about 5.5 when said mixture is added to water.
 14. Theanhydrous mixture of claim 11, wherein said buffer includessubstantially anhydrous citric acid and substantially anhydrous sodiumcitrate.
 15. The anhydrous mixture of claim 11, further including apharmaceutically acceptable anti-foaming agent.
 16. The anhydrousmixture of claim 15, wherein said anti-foaming agent ispolydimethylsiloxane.
 17. The anhydrous mixture of claim 11, furtherincluding a pharmaceutically acceptable dye.
 18. The anhydrous mixtureof claim 11, wherein said virginiamycin is substantially pure.
 19. Asubstantially anhydrous mixture comprising: a) virginiamycin; b) apharmaceutically acceptable and substantially anhydrous surfactantincluding sodium lauryl sulfate; c) a sufficient amount ofpharmaceutically acceptable buffering agent to provide a pH of fromabout 3.0 to about 7.0 when said mixture is added to water; d) fromabout 0.5 weight percent to about 10.0 weight percent colloidal silicondioxide; e) a pharmaceutically acceptable anti-foaming agent; and f) apharmaceutically acceptable dye. wherein the ratio of the weight percentof (b) to the weight percent of (a) percent by weight is at least about1 5:1.
 20. The anhydrous mixture of claim
 19. wherein the ratio of (b)to (a) is about 1 54:1
 21. The anhydrous mixture of claim 19, where theamount of buffer is sufficient to provide a pH of from about 4 0 toabout 5.5 when said mixture is added to water.
 22. The anhydrous mixtureof claim 19, wherein said buffer includes substantially anhydrous citricacid and substantially anhydrous sodium citrate.
 23. The anhydrousmixture of claim 19, wherein said anti-foaming agent ispolydimethylsiloxane.
 24. The anhydrous mixture of claim 19, whereinsaid virginiamycin is substantially pure.
 25. Feed grain treated with awater suspension of a mixture comprising: a) virginiamycin; b) apharmaceutically acceptable surfactant including sodium lauryl sulfate;c) a sufficient amount of pharmaceutically acceptable buffering agent tomaintain said suspension at a pH of from about 3.0 to about 7.0; d) fromabout 0.5 weight percent to about 10.0 weight percent colloidal silicondioxide, wherein the ratio of the weight percent of (b) to the weightpercent of (a) percent by weight is at least about 1.5:1.
 26. The feedgrain of claim 25, wherein the ratio of (b) to (a) is about 1.54:1. 27.The feed grain of claim 25, where the amount of buffer is sufficient toprovide a pH of from about 4.0 to about 5.5 in said suspension.
 28. Thefeed grain of claim 25, wherein said buffer includes citric acid andsodium citrate.
 29. The feed grain of claim 28, wherein the citric acidand sodium citrate is substantially anhydrous.
 30. The feed grain ofclaim 25, said mixture further including a pharmaceutically acceptabledye.
 31. The feed grain of claim 25, wherein said virginiamycin issubstantially pure
 32. The feed grain of claim 25, further including apharmaceutically acceptable anti-foaming agent in said mixture.
 33. Thefeed grain of claim 32, wherein said antifoaming agent ispolydimethylsiloxane.
 34. A method of treating feed grain withvirginiamycin, comprising (1) forming a mixture including: a)virginiamycin, b) a pharmaceutically acceptable surfactant includingsodium lauryl sulfate, c) a sufficient amount of pharmaceuticallyacceptable buffering agent to provide a pH of from about 3.0 to about7.0 when said mixture is added to water, and d) from about 0.5 weightpercent to about 10.0 weight percent colloidal silicon dioxide, whereinthe ratio of the weight percent of (b) to the weight percent of (a)percent by weight is at least about 1.5:1; (2) suspending said mixturein water to form a suspension; and (3) applying said suspension to feedgrain.
 35. The method of claim 34, wherein the ratio of (b) to (a) insaid mixture is about 1.54:1.
 36. The method of claim 34, wherein theamount of buffer in said mixture is sufficient to provide a pH of fromabout 4.0 to about 5.5 when said mixture is added to water.
 37. Themethod of claim 34, wherein said buffer in said mixture includes citricacid and sodium citrate.
 38. The method of claim 37, wherein said citricacid and sodium citrate are substantially anhydrous.
 39. The method ofclaim 34, further including a pharmaceutically acceptable anti-foamingagent in said mixture.
 40. The method of claim 39, wherein saidanti-foaming agent is polydimethylsiloxane.
 41. The method of claim 34,further including a pharmaceutically acceptable dye in said mixture. 42.The method of claim 34, wherein said virginiamycin in said mixture ISsubstantially pure.
 43. The method of claim 34, wherein said mixture issubstantially anhydrous
 44. The method of claim 34, wherein saidapplying step includes spraying the feed grain with said suspension. 45.The method of claim 34, further including drying the feed grain afterthe applying step.